Serious side effects may include seizures, increased risk of serotonin syndrome, decreased alertness, and drug addiction,[2] although the risk of serotonin syndrome appears to be low.[9] Common side effects include: constipation, itchiness and nausea, among others. A change in dosage may be recommended in those with kidney or liver problems.[2] It is not recommended in those who are at risk of suicide.[2] While not recommended in women who are breastfeeding, those who take it should not stop breastfeeding.[10]

Tramadol is marketed as a racemic mixture of both R- and S-stereoisomers.[3] This is because the two isomers complement each other's analgesic activity.[3] It is often combined with paracetamol (acetaminophen) as this is known to improve the efficacy of tramadol in relieving pain.[3] Tramadol is metabolized to O-desmethyltramadol, which is a more potent opioid.[11] It is of the benzenoid class.

Medical uses

Generic tramadol HCl tablets marketed by Amneal Pharmaceuticals.

Tramadol HCl for injection

Tramadol is used primarily to treat mild–severe pain, both acute and chronic.[12][13]

Its analgesic effects take about one hour to come into effect and 2–4 hours to peak after oral administration with an immediate-release formulation.[12] On a dose-by-dose basis tramadol has about one-tenth the potency of morphine and is approximately equally potent when compared to pethidine and codeine.[14]

For pain moderate in severity its effectiveness is equivalent to that of morphine; for severe pain it is less effective than morphine.[12] These painkilling effects peak at about 3 hours, post-oral administration and last for approximately 6 hours.[13]

Pregnancy and lactation

Tramadol's use in pregnancy is generally avoided as it may cause some reversible withdrawal effects in the newborn.[15] A small prospective study in France found that, while there was an increased risk of miscarriages, there were no major malformations reported in the newborn.[15] Its use during lactation is also generally advised against, but a small trial found that infants breastfed by mothers taking tramadol were exposed to about 2.88% of the dose the mothers were taking. There was no evidence of this dose having a harmful effect on the newborn.[15]

Labour and delivery

Its use as an analgesic during labour is generally advised against due to its long-onset of action (one hour).[15] The ratio of the mean concentration of the drug in the fetus compared to that of the mother when it is given intramuscularly for labour pains has been estimated to be 94.[15]

Fibromyalgia

As of 2015 tramadol was not approved in the United States for fibromyalgia.[16] Based on three small trials with weak study design, tramadol might be useful as a second line treatment.[16]

Children

Its use in children is generally advised against, although it may be done under the supervision of a specialist.[12] On September 21, 2015 the FDA started investigating the safety of tramadol in use in persons under the age of 17. The investigation was initiated because some of these people have experienced slowed or difficult breathing.[17]

Elderly

There is an increased risk of opioid-related adverse effects such as respiratory depression, falls, cognitive impairment and sedation.[12]

Liver and kidney failure

It is advised that the drug be used with caution in those with liver or kidney failure, due to the high dependence of the drug on the liver and kidneys for metabolism to O-desmethyltramadol and elimination, respectively.[12]

There are suggestions that chronic opioid administration may induce a state of immune tolerance,[21] although tramadol, in contrast to typical opioids, may enhance immune function.[22][23][24] Some have also stressed the negative effects of opioids on cognitive functioning and personality.[25]

Contraindications

Use of tramadol is not advised for people deficient in CYP2D6 enzymes which accounts for about 6–10% of Caucasians and 1–2% of Asians, as they are crucial to the therapeutic effects of tramadol, by means of enabling tramadol's metabolism to O-desmethyltramadol.[12]

Overdose

Fatalities with tramadol overdose have been reported and are increasing in frequency in Northern Ireland; the majority of these overdoses involve other drugs including alcohol.[29] Recognised risk factors for tramadol overdose include depression, addiction and seizures.[29]Naloxone only partially reverses the toxic effects of tramadol overdose and may increase the risk of seizures.[12]

Physical dependence and withdrawal

Long-term use of high doses of tramadol will cause physical dependence and a withdrawal syndrome.[30] These include both withdrawal symptoms typical of opioid withdrawal and those associated with SSRI withdrawal, including numbness, tingling, paresthesia, and tinnitus.[31] Psychiatric symptoms may include hallucinations, paranoia, extreme anxiety, panic attacks, and confusion.[32] In most cases, tramadol withdrawal will set in 12–20 hours after the last dose, but this can vary.[31] Tramadol withdrawal lasts longer than that of other opioids; seven days or more of acute withdrawal symptoms can occur as opposed to typically three or four days for other codeine analogues.[31]

However, according to a 2014 report by the World Health Organizations Expert Committee on Drug Dependence '"....in many cases of Tramadol dependence, a history of substance abuse is present....but....the evidence for physical dependence was considered minimal. Consequently, Tramadol is generally considered as a drug with low potential for dependence. In a recent German study (including a literature study, an analysis of two drug safety databases, and questionnaires analyses), the low abuse and low dependence potential of Tramadol were re-confirmed. The German expert group found a low prevalence of abuse or dependence in clinical practice in Germany, and concluded that Tramadol has a low potential for misuse, abuse, and dependence in Germany”.[33]

Psychological dependence and recreational use

Because of the possibility of convulsions at high doses for some users, recreational use can be very dangerous.[34] Tramadol can cause a higher incidence of nausea, dizziness, loss of appetite compared with opioids, which could deter recreational use.[35] Compared to hydrocodone, fewer persons choose to use tramadol recreationally.[36]

It may also have a large effect on sleeping patterns and high doses may cause insomnia, especially for those on methadone, both for maintenance and recreation. Though there is no scientific proof tramadol lessens effects of opiates or is a mixed agonist-antagonist, some people get the impression it is, while someone else might benefit being prescribed both for pain and breakthrough pain.[28]

Detection in biological fluids

Tramadol and O-desmethyltramadol may be quantified in blood, plasma or serum to monitor for abuse, confirm a diagnosis of poisoning or assist in the forensic investigation of a traffic or other criminal violation or a sudden death. Most commercial opiate immunoassay screening tests do not cross-react significantly with tramadol or its major metabolites, so chromatographic techniques must be used to detect and quantitate these substances. The concentration of O-desmethyltramadol in the blood or plasma of a person who has taken tramadol is generally 10–20% those of the parent drug.[37][38][39]

Chemistry

Synthesis and stereoisomerism

(1R,2R)-tramadol

(1S,2S)-tramadol

(1R,2S)-tramadol

(1S,2R)-tramadol

The chemical synthesis of tramadol is described in the literature.[40] Tramadol [2-(dimethylaminomethyl)-1-(3-methoxyphenyl)cyclohexanol] has two stereogenic centers at the cyclohexane ring. Thus, 2-(dimethylaminomethyl)-1-(3-methoxyphenyl)cyclohexanol may exist in four different configurational forms:

(1R,2R)-isomer

(1S,2S)-isomer

(1R,2S)-isomer

(1S,2R)-isomer

The synthetic pathway leads to the racemate (1:1 mixture) of (1R,2R)-isomer and the (1S,2S)-isomer as the main products. Minor amounts of the racemic mixture of the (1R,2S)-isomer and the (1S,2R)-isomer are formed as well. The isolation of the (1R,2R)-isomer and the (1S,2S)-isomer from the diastereomeric minor racemate [(1R,2S)-isomer and (1S,2R)-isomer] is realized by the recrystallization of the hydrochlorides.
The drug tramadol is a racemate of the hydrochlorides of the (1R,2R)-(+)- and the (1S,2S)-(–)-enantiomers.
The resolution of the racemate [(1R,2R)-(+)-isomer / (1S,2S)-(–)-isomer] was described[41] employing (R)-(–)- or (S)-(+)-mandelic acid. This process does not find industrial application, since tramadol is used as a racemate, despite known different physiological effects[42] of the (1R,2R)- and (1S,2S)-isomers, because the racemate showed higher analgesic activity than either enantiomer in animals[43] and in humans.[44]

Its analgesic effects are only partially reversed by naloxone, hence indicating that its opioid action is unlikely the sole factor; tramadol's analgesic effects are also partially reversed by α2 adrenergic receptor antagonists like yohimbine and the 5-HT3 receptor antagonist, ondansetron.[13] Pharmacologically, tramadol is similar to levorphanol and tapentadol in that it not only binds to the mu opioid receptor, but also inhibits the reuptake of serotonin and norepinephrine[3] due to its action on the noradrenergic and serotonergic systems, such as its "atypical" opioid activity.[59]

Tramadol has inhibitory actions on the 5-HT2C receptor. Antagonism of 5-HT2C could be partially responsible for tramadol's reducing effect on depressive and obsessive-compulsive symptoms in patients with pain and co-morbid neurological illnesses.[52] 5-HT2C blockade may also account for its lowering of the seizure threshold, as 5-HT2Cknockout mice display significantly increased vulnerability to epileptic seizures, sometimes resulting in spontaneous death. However, the reduction of seizure threshold could be attributed to tramadol's putative inhibition of GABAA receptors at high doses.[51] In addition, tramadol's major active metabolite, O-desmethyltramadol, is a high-affinity ligand of the δ- and κ-opioid receptors, and activity at the former receptor could be involved in tramadol's ability to provoke seizures in some individuals, as δ-opioid receptor agonists are well known to induce seizures.[60]

Pharmacokinetics

O-desmethyltramadol

Tramadol undergoes hepatic metabolism via the cytochrome P450isozymeCYP2B6, CYP2D6 and CYP3A4, being O- and N-demethylated to five different metabolites. Of these, O-desmethyltramadol is the most significant since it has 200 times the μ-affinity of (+)-tramadol, and furthermore has an elimination half-life of nine hours, compared with six hours for tramadol itself. As with codeine, in the 6% of the population that have reduced CYP2D6 activity (hence reducing metabolism), there is therefore a reduced analgesic effect. Those with decreased CYP2D6 activity require a dose increase of 30% in order to achieve the same degree of pain relief as those with a normal level of CYP2D6 activity.[61][62]

Phase II hepatic metabolism renders the metabolites water-soluble, which are excreted by the kidneys. Thus, reduced doses may be used in renal and hepatic impairment.[13]

Society and culture

Legal status

The U.S. Food and Drug Administration (FDA) approved tramadol in March 1995 and an extended-release (ER) formulation in September 2005.[63] Tramadol is protected by US patents nos. 6,254,887[64] and 7,074,430.[65][66] The FDA listed the patents' expiration as 10 May 2014.[65] However, in August 2009, US District Court for the District of Delaware ruled the patents invalid, which, if it survives appeal, would permit manufacture and distribution of generic equivalents of Ultram ER in the United States.[67]

Effective August 18, 2014, tramadol has been placed into Schedule IV of the federal Controlled Substances Act.[68][69] In addition, many states, including Arkansas, Georgia, Kentucky, Illinois, Mississippi, New York, North Dakota, Ohio, Oklahoma, South Carolina, Tennessee, West Virginia, Wyoming and the U.S. military have already classified tramadol as a Schedule IV controlled substance under state law.[70][71][72]

Pin cushion tree

In 2013, researchers reported that tramadol was found in relatively high concentrations (1%+) in the roots of the African pin cushion tree (Nauclea latifolia).[76] In 2014, however, it was reported that the presence of tramadol in the tree roots was the result of tramadol having been administered to cattle by farmers in the region:[77] tramadol and its metabolites were present in the animals' excreta, which contaminated the soil around the trees. Therefore, tramadol and its mammalian metabolites were found in tree roots in the far North of Cameroon, but not in the South where it is not administered to farm animals.[77]

A 2014 editorial in Lab Times online contested the notion that tramadol in tree roots was the result of anthropogenic contamination, stating that samples were taken from trees which grew in national parks, where livestock were forbidden; it also quoted researcher Michel de Waard, who stated that "thousands and thousands of tramadol-treated cattle sitting around a single tree and urinating there" would be required to produce the concentrations discovered.[78]

In 2015, radiocarbon analysis confirmed that the Tramadol found in S.latifolius seeds cannot be plant-derived and is of synthetic origin.[79]